bims-unfpre Biomed News
on Unfolded protein response
Issue of 2026–05–10
eight papers selected by
Susan Logue, University of Manitoba
  1. CDS-localized m6A drives co-translational RNA decay to relieve biotic and abiotic endoplasmic reticulum stresses.
  2. Discovery of a pyrazolopyridine alkaloid that mitigates neuronal ER stress and age-related decline.
  3. Coronavirus M protein disperses the trans-Golgi network and inhibits anterograde protein trafficking in the secretory pathway.
  4. Signal peptide peptidase-like proteases OsSPPL1 and OsSPPL2 facilitate ER-associated protein degradation in rice.
  5. The Role of ER Stress in Bilirubin Neurotoxicity: A Complex Molecular Network.
  6. A microRNA generated via lysosomal processing of ribosomal RNA suppresses proinflammatory responses.
  7. Targeting the IRE1α-XBP1 signaling axis impairs tumor growth and promotes myogenic differentiation in rhabdomyosarcoma.
  8. Taxane chemotherapy promotes response to TIM-3 checkpoint blockade via STING-mediated ER stress and HMGB1 secretion.
  1. Nat Plants. 2026 May 08.
    CDS-localized m6A drives co-translational RNA decay to relieve biotic and abiotic endoplasmic reticulum stresses.
    Songxiao Zhong, Tae Rin Oh, Xindi Li, Jinming Zhang, Suk Won Choi, Chuyun Gao, Xu Peng, Juan Dong, Chuan He, Xiuren Zhang.
      The endoplasmic reticulum (ER) mitigates stress typically through unfolded protein response (UPR) and ER-associated degradation (ERAD) pathways, yet post-transcriptional regulation of ER stress remains poorly defined. N6-methyladenosine (m6A) modification, predominantly enriched near stop codons, can govern mRNA fates via P-bodies or stress granules in stress conditions. m6A also occurs within coding sequences (CDS-m6A), but its role remains unappreciated in plants. Here we demonstrate that m6A ablation sensitizes Arabidopsis ER stress despite normal UPR and ERAD activities. Mechanistically, CDS-m6A co-localizes with ribosome stalling sites and directs co-translational RNA decay (CTRD). Under stress, activation of m6A-triggered CTRD accelerates clearance of ER-engaged transcripts, thereby alleviating translational overload. During geminivirus infection, which increases translational demand on ER, m6A-triggered CTRD also targets viral RNAs, restricting their accumulation, translation and disease progression. Thus, CDS-m6A functions as a pivotal regulator of ER-linked RNA surveillance, establishing an organelle-specific mechanism that integrates RNA stability, protein homeostasis and antiviral defence.
    DOI:  https://doi.org/10.1038/s41477-026-02299-4
  2. Commun Biol. 2026 May 08.
    Discovery of a pyrazolopyridine alkaloid that mitigates neuronal ER stress and age-related decline.
    Salinee Jantrapirom, Apiwat Sangphukieo, Natsinee U-On, Pattaporn Poonsawas, Wasinee Wongkumool, Ranchana Yeewa, Chansunee Panto, Puttachat Poound, Ester Zito, Alice Marrazza, Luca Lo Piccolo.
      Endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative and age-associated diseases, motivating the search for compounds that enhance ER-stress resilience. Modulation of ER-redox pathways, including those associated with the oxidase ERO1A, can attenuate maladaptive unfolded protein response (UPR) signaling and improve cellular stress tolerance. Here we develop an integrative discovery strategy to identify natural compounds that mitigate ER-stress-associated phenotypes across cellular and organismal models. Structure-informed virtual screening guided by ERO1A biology prioritized the pyrazolopyridine alkaloid S88. In human SH-SY5Y-derived neurons, S88 improves survival and reduces tunicamycin-induced ER-stress markers. In Drosophila, S88 ameliorates neuromuscular and locomotor phenotypes in a UBQLN2-associated ALS model and improves aging-related outcomes. Biochemical assays did not detect inhibition of ERO1A or radical scavenging activity by S88, indicating that its molecular target remains to be identified. Together, these findings identify S88 as a natural-product scaffold that enhances ER-stress resilience across neuronal and in vivo models.
    DOI:  https://doi.org/10.1038/s42003-026-10226-8
  3. PLoS Pathog. 2026 May 05. 22(5): e1014117
    Coronavirus M protein disperses the trans-Golgi network and inhibits anterograde protein trafficking in the secretory pathway.
    Taylor M Caddell, Rory P Mulloy, Jennifer A Corcoran, Eric S Pringle, Craig McCormick.
      Coronaviruses (CoVs) encode a variety of transmembrane proteins that are translated and processed at the endoplasmic reticulum (ER). Three host ER resident transmembrane proteins, activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1), and PKR-like endoplasmic reticulum kinase (PERK), sense the accumulation of unfolded proteins in the ER and initiate the unfolded protein response (UPR) to maintain ER proteostasis. We observed that SARS-CoV-2 Spike broadly activated all three arms of the UPR, whereas the Membrane (M) protein selectively inhibited ATF6. ATF6 has a unique activation mechanism whereby ER stress triggers translocation to the Golgi where ATF6 is processed by resident proteases to release the ATF6-N transcription factor. We observed that M inhibited the stress-induced production of ATF6-N, suggesting that ATF6 failed to engage with Golgi proteases for processing. M also inhibited sterol regulatory element binding protein-2 (SREBP2)-mediated activation of sterol responses and stimulator of interferon response cGAMP interactor 1 (STING)-mediated activation of interferon responses, both of which are activated in the ER and require translocation to the Golgi for interactions that yield transcriptional responses. We observed that M accumulated in the cis-Golgi, and triggered dispersal of the trans-Golgi network (TGN). Using a cargo sorting assay, we determined that ER-to-Golgi cargo trafficking was intact in the presence of M, but cargo accumulated with M in the cis-Golgi and did not proceed further in the secretory pathway. We also observed aberrant cholesterol accumulation at the cis-Golgi with M, consistent with our observation of M association with detergent resistant membranes. Together, these data suggest that CoV M proteins interfere with Golgi architecture and trafficking. Because CoV egress does not require the canonical secretory pathway, this mechanism could allow the virus to selectively interfere with host responses to infection without impeding egress of nascent virions.
    DOI:  https://doi.org/10.1371/journal.ppat.1014117
  4. Nat Commun. 2026 May 07.
    Signal peptide peptidase-like proteases OsSPPL1 and OsSPPL2 facilitate ER-associated protein degradation in rice.
    Hai-Ping Lu, Jian-Hang Xu, Jia-Xin Chang, Hui-Dan Luo, Jian-Xiang Liu.
      Signal peptide peptidases (SPPs) play a critical role in intramembrane proteolysis of signal peptides in mammals. However, their function in plants remains poorly understood. Here, we uncover the critical role of two rice SPP-like proteins, OsSPPL1/ 2, in ER-associated degradation (ERAD). Their expression is directly upregulated by OsbZIP50 under ER stress conditions. Mutations in OsSPPL1/2 result in increased ER stress sensitivity, whereas their overexpression enhance ER stress tolerance. We further demonstrate that OsSPPL1/2 localize in ER, and physically interact with the ERAD components OsDER1/2, indicating their involvement in ERAD. Using a GFP protein fused with a segment of maize floury-2 protein defective in signal peptide cleavage (ZmFL2m-GFP), we show that OsSPPL1/2 interact with ZmFL2m-GFP in ER and facilitate its degradation in tobacco leaves and rice plants. Additionally, OsSPPL1/2 double mutants exhibit exaggerated thermal sensitivity, while OsSPPL1/2-overexpressing plants display improved thermotolerance. Together, our findings identify OsSPPL1/2 as components of ERAD and highlight the importance of ERAD in plant thermotolerance.
    DOI:  https://doi.org/10.1038/s41467-026-72830-w
  5. Antioxidants (Basel). 2026 Apr 03. pii: 451. [Epub ahead of print]15(4):
    The Role of ER Stress in Bilirubin Neurotoxicity: A Complex Molecular Network.
    Mohammed Qaisiya, Claudio Tiribelli, Cristina Bellarosa.
      Although the molecular pathogenesis of bilirubin-induced neuronal cell injury is not completely understood, certain recurrent themes resonate in the literature on this topic and include the generally untoward effects of high unconjugated bilirubin (UCB) concentrations on membranes (plasma, mitochondrial, and endoplasmic reticulum (ER)), cellular bioenergetics, and intracellular calcium homeostasis. Only in the last decade, ER was discovered as an early target of bilirubin neurotoxicity. We will review the main features of bilirubin neurotoxicity from the point of view of ER and bilirubin-induced ER stress. Neuronal excitotoxicity, mitochondrial energy failure, and increased intracellular calcium concentration are three phenomena linked spatially and temporally in the pathogenesis of bilirubin-induced neurotoxicity. ER, being the main intracellular calcium storage organelle, is involved in the increase in the universal second messenger, calcium. This event leads to the activation of proteolytic enzymes, apoptotic pathways, and necrosis, the occurrence of which is likely a function of the degree and duration of bilirubin exposure.
    Keywords:  calcium homeostasis; endoplasmic reticulum stress; neuroinflammation; neurotoxicity; unconjugated bilirubin
    DOI:  https://doi.org/10.3390/antiox15040451
  6. Life Sci Alliance. 2026 Jul;pii: e202503536. [Epub ahead of print]9(7):
    A microRNA generated via lysosomal processing of ribosomal RNA suppresses proinflammatory responses.
    Dan Michael, Ester Feldmesser, K Shanmugha Rajan, Yoav Lubelsky, Anat Bashan, Alexandros Damalas, Shiri Ben Zvi, Aya Friedberg, Netta Eitan, Shachar Erez, Ada Yonath, Igor Ulitsky, Moshe Oren.
      ER stress underlies numerous severe pathologies. We have metabolically perturbed normal fibroblasts to study the biological roles of microRNAs (miRs) under mild and extended ER stress. We now report that miR-4488 quenches inflammation-associated gene expression in such metabolically perturbed cells. Remarkably, generation of miR-4488 is Drosha-independent. Furthermore, we define miR-4488 as a noncanonical miRNA derived from the expansion segment ES7L of the 28S ribosomal RNA. Moreover, its generation involves the autophagy-lysosome route and is inhibited when this pathway is blocked, thus unveiling an anti-inflammatory role for ribosomal RNA and lysosomes, engaged at the onset of stress. Mechanistically, miR-4488 suppresses the expression of NFKB2 and RELB, whose mRNAs specifically associate with miR-4488 exclusively upon stress. This selectivity suggests that miR-4488 may bear promise for treating mild ER stress-associated diseases.
    DOI:  https://doi.org/10.26508/lsa.202503536
  7. Commun Biol. 2026 May 06.
    Targeting the IRE1α-XBP1 signaling axis impairs tumor growth and promotes myogenic differentiation in rhabdomyosarcoma.
    Anh Tuan Vuong, Aniket S Joshi, Phuong T Ho, Meiricris Tomaz da Silva, Bin Guo, Meghana V Trivedi, Ashok Kumar.
      Rhabdomyosarcoma (RMS) is a pediatric soft-tissue sarcoma arising from mesenchymal progenitors with skeletal muscle features. The unfolded protein response (UPR) maintains proteostasis during endoplasmic reticulum stress, with the IRE1α-XBP1 axis representing a key signaling branch. Here, we demonstrate that components of this pathway are significantly upregulated in RMS cell lines and primary tumors. Genetic or pharmacological inhibition of IRE1α or spliced XBP1 (sXBP1) suppresses cell proliferation, promotes terminal myogenic differentiation, and enhances vincristine-induced cytotoxicity in RMS cells. Silencing of sXBP1 further reduces the cancer stem-like cell population and impairs migration and invasion. Mechanistically, IRE1α-XBP1 signaling promotes RMS progression through sXBP1-dependent upregulation of BMPR1A and subsequent activation of BMP-SMAD1 signaling. Consistently, inducible knockdown of sXBP1 or pharmacological inhibition of IRE1α endonuclease activity significantly attenuates xenograft RMS growth. Collectively, these findings identify the IRE1α-XBP1 axis as a critical regulator of RMS growth, differentiation, and chemosensitivity, and support its therapeutic targeting in RMS.
    DOI:  https://doi.org/10.1038/s42003-026-10184-1
  8. Cell Rep Med. 2026 May 06. pii: S2666-3791(26)00205-3. [Epub ahead of print] 102788
    Taxane chemotherapy promotes response to TIM-3 checkpoint blockade via STING-mediated ER stress and HMGB1 secretion.
    Alexis Onimus, Daiana Celias, Shiun Chang, Joshua Davis, Jay Mandula, Jie Li, Alycia Gardner, Kay Hänggi, Olabisi Osunmakinde, Hatem Soliman, Timothy I Shaw, Paulo C Rodriguez, Brian Ruffell.
      Immune checkpoint inhibitors are increasingly being used in conjunction with chemotherapy regimens, but the reasons for the success or failure of these combinations remains unclear. In previous studies, we described how blocking TIM-3 promotes activation of dendritic cells through HMGB1-dependent DNA uptake, resulting in efficacy when combined with paclitaxel. Here, we show that the release of HMGB1 by tumor cells is required for the combinatorial efficacy with TIM-3 blockade observed with paclitaxel, docetaxel, fluorouracil, and irradiation. HMGB1 release during taxane therapy is an active process involving nuclear export following Toll-like receptor 4 (TLR4)-dependent reactive oxygen species production, DNA damage, and poly(ADP-ribose) polymerase activation. DNA damage promotes the accumulation of cytosolic double-stranded DNA (dsDNA), which activates the cGAS-STING pathway; however, taxanes fail to induce type I interferons. Instead, STING activation promotes endoplasmic reticulum (ER) stress and lysosomal exocytosis, driving HMGB1 secretion. Thus, non-canonical STING signaling in response to taxanes can promote the efficacy of chemoimmunotherapy.
    Keywords:  DNA damage; HMGB1; STING; TIM-3; TLR4; cGAS; chemotherapy; paclitaxel
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102788
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒10 at 17:26.